Fusarium Infections in Critically Ill Patients

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- Kimberly Dawley

Monday, March 09, 2009 12:22 PM

http://www.imakenews.com/pureaircontrols/e_article000328271.cfm?x=b11,0,w

Fusarium Infections in Critically Ill Patients by Michail S. Lionakis, M.D.; Dimitrios P. Kontoyiannis, M.D., Sc.D., F.A.C.P.

Abstract and IntroductionAbstract Invasive mold infections (IMIs) are significant causes of infectious mortality in immunocompromised patients, such as those with hematologic malignancies and allogeneic bone marrow transplant recipients. Of the IMIs, invasive aspergillosis is by far the most common. Nevertheless, over the past decade, other filamentous molds, such as Fusarium species, have been increasingly reported as the cause of severe IMIs in these patient populations. Herein we critically review the epidemiology, pathogenesis, clinical presentation, diagnostic methods, and therapeutic approaches for invasive fusariosis in immunocompromised hosts. We also present the key characteristics and differentiating features of invasive fusariosis and invasive aspergillosis. Current therapeutic approaches for fusariosis are suboptimal, resulting in exceedingly high mortality rates. At present, prompt diagnosis along with rapid initiation of appropriate treatment and, more importantly, reconstitution of the host immune responses are critical for a favorable outcome of this devastating opportunistic mycosis.Introduction Even though filamentous molds are ubiquitous in the environment, only over the past 2 decades have such saprophytic fungi emerged as a major threat in patients with compromised host defenses, such as those with hematologic malignancies and bone marrow transplant (BMT) recipients.[1-3] Aspergillus is by far the most common mold causing severe infections. However, other fungi, such as Fusarium species, have been increasingly recognized as lethal pathogens in these patients.[1,2,4-9] This shift is multifactorial yet not surprising because it reflects the use of new, highly immunosuppressive chemotherapeutic regimens and the broad use of antifungal agents as either or both prophylactic and empiric therapy, resulting in selection of more resistant fungi.[1-9] In this article, we critically review the epidemiology, pathogenesis, clinical manifestations, diagnostic tools, and therapeutic options for invasive fusariosis with a focus on the major characteristics that differentiate between invasive fusariosis and invasive aspergillosis (IA).Epidemiology Fusarium spp. have long been recognized as soil saprophytes and plant and bacterial pathogens.[6,9-11] Among the 50 different species of the Fusarium genus, only a few have been reported to be pathogenic in humans: Fusarium solani, Fusarium oxysporum, Fusarium moniliforme, Fusarium verticilloides, Fusarium dimerum, and Fusarium proliferatum.[5-8,10-12] Among these, F. solani causes half of the reported human invasive fusariosis cases. This is consistent with its higher virulence in a murine model of disseminated fusariosis.[13] The incidence of fusariosis in humans is not clear, however, because systematic reporting of this infection has not been performed. Since the description of the first case of disseminated fusariosis in a child with acute leukemia in 1973,[14] reports of this opportunistic mycosis have dramatically increased; in fact, invasive fusariosis has emerged in many tertiary-care cancer centers as the second most common invasive mold infection (IMI) in profoundly immunocompromised patients behind IA.[1,2,4-8,10-12,15-22]There seems to be a distinct seasonal peak and geographic distribution of invasive fusariosis.[7,8] Specifically, the majority of the cases occur during the rainy summer season, when the dispersion of fusarial conidia in the air is more pronounced.[4,7,8] Moreover, the vast majority of fusariosis cases have been reported in the United States.[7,8] It remains unclear, however, whether this reflects a unique ecological niche for these molds or a reporting bias. Even within the United States, the epidemiologic distribution of invasive fusariosis is heterogeneous because most cases have been reported in certain oncology centers, such as ours.[4] Outside the United States, most of the cases of invasive fusariosis have been reported in the Mediterranean region (i.e., Italy and France) and Brazil.[7,8,22]The skin and respiratory tract are the primary portals of entry for Fusarium infection.[4,7-9,19-26] For instance, the use of central venous catheters (CVCs) and continuous ambulatory peritoneal dialysis catheters has been associated with invasive fusariosis.[23,24] Moreover, patients with extensive burns are susceptible to colonization by Fusarium spp. and may develop an invasive soft tissue infection leading to subsequent disseminated fusariosis.[25] Localized skin and nail infections have also been associated with subsequent dissemination of Fusarium spp. when the patient becomes neutropenic during the course of immunosuppressive treatment.[26,27] Besides through the skin, the preponderant entry of Fusarium infection is via inhalation of Fusarium conidia from the environment.[4-9,10-12,15-18] Less frequently, the paranasal sinuses and gastrointestinal tract have been presumed to be portals of entry for fusariosis.[4,9] In addition, documented nosocomial Fusarium infections have been reported, such as postoperative endophthalmitis and osteomyelitis.[9,28] Hospital water distribution systems have recently been implicated as sources of nosocomial fusariosis.[29] However, another epidemiologic analysis did not confirm this assertion.[30] Hence, more rigorous studies are required to elucidate this controversy.Pathogenesis of Invasive Fusariosis: Patient Populations at Risk As with Aspergillus species, there are two developmental programs of growth of Fusarium spp., conidia, and hyphae. In immunocompetent hosts, there are two lines of defense against inhaled Fusarium conidia.[31] First, the resident lung macrophages are responsible for phagocytosis and, primarily, nonoxidative killing of conidia.[31,32] Despite the efficiency of phagocytosis, some conidia ultimately escape, germinate to hyphae, and establish an invasive infection. Use of glucocorticoids predisposes patients to fusariosis mainly via impairment of the anticonidial macrophage function.[33] A recent multicenter study showed that the mortality rate for fusariosis was 70% in hematologic cancer patients receiving glucocorticoids compared with 33% in patients not receiving glucocorticoids.[34] Once an infection is established, neutrophils are chemotactically attracted to the hyphae on which they attach. Fusarium hyphae are subsequently destroyed extracellularly by the oxidative cytotoxic mechanisms of neutrophils.[31,32] Neutrophils probably play the most critical role in the control of human Fusarium infections.[4-8,10-12,15-22,34,35] Several studies have demonstrated that the prognosis for patients with fusariosis is clearly associated with prompt recovery of neutrophil counts. In fact, the mortality rate for fusariosis in the setting of profound, prolonged neutropenia is essentially 100%, even with aggressive antifungal treatment, whereas it has been reported to be as low as 30% when neutrophil counts are or promptly return to normal. Relapses following subsequent episodes of neutropenia have also been reported.[4]More than 90% of human invasive fusariosis cases occur in neutropenic patients with hematologic malignancies, especially those with acute leukemia, in whom over 50% of all cases have been reported.[4,7-9,10-12,16-20] Moreover, allogeneic BMT recipients are at risk for fusariosis, especially in the early posttransplant period when engraftment is delayed and later in the setting of iatrogenic hypercortisolism for the treatment of acute or chronic graft-versus-host disease.[4,10-12,21] It has been estimated that the incidence of fusariosis in allogeneic and autologous BMT recipients is 1.2% and 0.2%, respectively.[4] However, host-specific differences in the manifestation of Fusarium infections do exist. For example, Fusarium infections in solid-organ transplant recipients tend to remain localized, occur late in the posttransplant period (>9 months), and have a better outcome when compared with infections in allogeneic BMT recipients with graft-versus-host disease, which are characteristically disseminated and frequently fatal.[36,37] Also, patients with aplastic anemia, chronic granulomatous disease, or acquired immunodeficiency syndrome have a distinctly low incidence of fusariosis.[38-40]Except for defective host immune responses, the pathogenesis of fusariosis may also be related to several virulence characteristics of the individual Fusarium strains. For example, Fusarium spp. are capable of producing several mycotoxins.[41-43] Nelson et al[9] reported that such toxins may cause leukopenia, thus potentially prolonging chemotherapy-induced bone marrow suppression.[42] Nonetheless, the molecular events that control the production of such toxins have yet to be determined, and there have been no studies examining whether such mycotoxins are specifically expressed in the setting of invasive disease. In addition, F. solani has been reported to produce cyclosporine, which is known to suppress T lymphocyte activation and interleukin-2 production, thus inhibiting critical components of the cellular immune response.[44]Furthermore, like Aspergillus and Zygomycetes species, Fusarium spp. are angiotropic and angioinvasive molds that lead to hemorrhagic infarction, low tissue perfusion, and resultant tissue necrosis.[6,9,11] Whether the ability of Fusarium spp. to invade human tissues is associated with the production of cyclosporine, which has been shown to cause toxic effects on the human vasculature by impairing endothelium-dependent relaxation, remains to be determined.[45] The potential adhesive properties of Fusarium spp. may also contribute to the pathogenesis of fusariosis.[9,46] These molds can adhere to silastic catheters, and infections of CVCs, continuous ambulatory peritoneal dialysis catheters, and contact lenses have been reported.[9] Most of the evidence of these adhesive properties has been derived from animal models of Fusarium keratitis.[46] Specifically, the ability of Fusarium spp. to secrete proteinases with elastinolytic properties seems to play an important role in corneal ulceration. Also, the formation of hyphae-to-hyphae structures with thickened cell walls has been postulated to protect Fusarium spp. from the neutrophil insult.Clinical Presentation of Fusarium Infections in Critically Ill Patients The clinical manifestations of invasive fusariosis are often nonspecific, and the host status plays a crucial role in determining the severity, type, and chronicity of the infection.[2,4,5] In contrast with Fusarium infections in normal hosts, which are typically localized (e.g., skin and eye infections and osteomyelitis) and frequently do not require systemic therapy, fusariosis in profoundly immunocompromised patients manifests in four major patterns: refractory fever of unknown origin, sinopulmonary infection or pneumonia, disseminated infection, and a variety of focal single-organ infections.[2,5,9,10-12,15-23]The usual initial presentation of invasive fusariosis is a fever that persists despite broad-spectrum antimicrobial coverage in a profoundly neutropenic patient.[4,5] Because Fusarium spp. are often resistant to antifungal agents, breakthrough infections are not uncommon despite the use of prophylactic or empiric therapy with amphotericin B (AMB) or triazoles.[4,5,47,48] Also, pneumonia is frequently observed.[7,8] A study at the University of Texas M. D. Anderson Cancer Center revealed that more than 80% of the patients with invasive fusariosis had pulmonary involvement.[4] In the vast majority of those cases (80%), nonspecificinfiltrates were noted; less frequently, either or both nodular and cavitary lesions were seen. Most pulmonary infiltrates are bilateral.[4] Respiratory symptoms such as cough (typically dry) and dyspnea are common, and hemoptysis may also occur. Furthermore, the presence of friction rib is indicative of subpleural IMI. Sinus involvement is also frequent, observed in up to 80% of cases in some reports.[4-8] The maxillary sinus seems to be the site involved most frequently, with the ethmoid sinuses being the second most common site.[4] Sinopulmonary fusariosis is most often clinically and radiographically indistinguishable from the much more common IA and other IMIs (Table 1).[4-9,10-12]Fusarium sinusitis and pneumonia can disseminate in the setting of continuous, profound immunosuppression. Other less common presentations of invasive fusariosis in compromised hosts include focal single-organ infections, such as osteomyelitis, septic arthritis, myositis, foot abscesses, myocarditis, external otitis, peritonitis, brain abscesses, cystitis, meningoencephalitis, and chronic hepatic infection.[4-8,16-22]Laboratory Diagnosis: Differential Diagnosis of Other Invasive Mold Mycoses One of the diagnostic challenges in immunocompromised patients with fungal pneumonia is differentiating between IA, invasive fusariosis, and zygomycosis. Zygomycosis is another emerging IMI that, in patients with hematologic malignancies, typically presents as sinopulmonary infection as opposed to the rhinocerebral form of the disease, which is encountered in patients with decompensated diabetes and ketoacidosis.[49] As described previously, the clinical and radiographic features of these IMIs are similar and nonspecific (Table 1).[3-5] Hence, it is almost impossible to establish a diagnosis on clinical grounds, and recovery of Fusarium spp. from cultures of appropriate specimens is essential for a definite diagnosis.[5]Biopsy analysis of Fusarium lesions usually reveals extensive necrosis surrounding the fungal elements consisting of acute branching septate hyphae.[5,8,9,11] The histopathologic picture is identical with that caused by Aspergillus and Pseudallescheria species and may lead to misidentification.[5] Even so, Liu et al[50] reported that there are subtle differences in the histopathologic features of Aspergillus and Fusarium spp. that can allow for differentiation between the two species based on the histopathology itself. Specifically, the hyphae of Fusarium spp. often exhibit variation in their diameter and typically manifest both 45 and 90 degree branching.[30] In comparison, Aspergillus spp. tend to form hyphae of a more consistent diameter and exhibit 90 degree branching much less frequently.[30] In contrast, the hyphae of Zygomycetes spp. are widely branching and nonseptate and tend to have a larger diameter; thus they can be easily discernible from hyphae of Aspergillus and Fusarium spp. In fact, the lack of septation of Zygomycetes broad hyphae leads to the absence of internal support and characteristically results in collapse and folding in a ribbonlike appearance.[30] Molecular methods show promise in differentiating Fusarium and Aspergillus species from histopathologic specimens. In a recent study, Hayden et al[51] demonstrated that in situ hybridization directed against ribosomal ribonucleic acid sequences can be used to rapidly and accurately distinguish Fusarium, Aspergillus, and Pseudallescheria spp. in tissue sections. Because the aforementioned molds have different levels of susceptibility to modern antifungals, the ability to differentiate these molds before culture results are available using in situ hybridization could have significant implications on therapeutic decision making.However, obtaining an appropriate culture of the infected tissue remains the gold standard for differentiation between Fusarium and Aspergillus spp. Microscopically, a Fusarium colony begins as a white patch that quickly develops a pink, purple, or yellow center with a lighter periphery.[5,9] There are three types of Fusarium conidia found in cultures: microconidia, macroconidia, and chlamydospores. The presence of canoe-shaped macroconidia is a key feature in characterizing the Fusarium genus.[5] When such macroconidia are absent, identification of Fusarium spp. is often difficult because confusion with other uncommon saprophytic molds, including Acremonium, Cylindrocarpon, and Verticillium species, may occur.[5,9,50] Other important morphological features of Fusarium spp. are the presence of microconidia and chlamydospores and the morphology of the conidiophores bearing the microconidia.[5,9] The colony color, length, and shape of the macroconidia and number, shape, and arrangement of the microconidia are also helpful in differentiating between the various Fusarium spp.[9] Nonetheless, this differentiation is not always easy based on culture analysis because of the propensity of Fusarium spp. to change morphology rapidly.[2,9,22,47,50] Thus, a reference laboratory is often required for identifying Fusarium spp.In addition to conventional isolation methods, molecular methods such as polymerase chain reaction have been used to improve diagnosis of fusariosis from clinical specimens such as blood or bronchoalveolar lavage.[52-54] Nonetheless, although polymerase chain reaction techniques have been proposed to have the potential to detect Fusarium spp. earlier, further studies are needed to define the sensitivity and specificity of such assays in detecting these species.Despite the clinical similarities of fusariosis and IA, there are some characteristics that favor the diagnosis of invasive fusariosis (see Table 1). First, Fusarium spp. are usually recovered from blood specimens in the setting of disseminated disease.[4,5,55-57] The reported rate of positive blood cultures in disseminated fusariosis is 50 to 70%, and fungemia may be the only manifestation of the infection. In fact, Fusarium spp. were identified as the most common molds associated with true fungemia in BMT recipients.[56] This feature contrasts with disseminated IA and zygomycosis cases, in which these molds are rarely isolated from blood specimens.[58] Specifically, less than 5% of cases of disseminated IA have positive blood cultures, and aspergillemia typically reflects contamination of the culture medium rather than a true infection.[58] Recovery of Aspergillus terreus from the blood is the notable exception because it frequently represents true fungemia.[58] Also of note is that Fusarium-positive blood cultures often become positive relatively early in the course of the disseminated disease as opposed to true Aspergillus fungemia, which manifests either shortly before death or postmortem.[4,55-58] This high frequency of Fusarium-positive blood cultures is presumed to be caused by the production of a large number of adventitious propagules in tissues by Fusarium spp.[4,5,9] This feature is common in yeasts but not in most of the pathogenic molds.[5] Exceptions to this rule are Acremonium, Paecilomyces, and Scedosporium species.[5,50] Others have suggested that toxins secreted by Fusarium spp. may lead to disruption of the vasculature and easier access of Fusarium conidia to the bloodstream.[10,41-43]Another distinctive feature of invasive fusariosis is the high incidence (50-70%) of skin lesions in the setting of disseminated disease.[59,60] This contrasts with the low incidence of skin lesions in disseminated aspergillosis (<10%).[3,5,59,60] In fact, skin lesions are frequently the sole diagnostic material for invasive fusariosis.[59,60] Several patterns of skin lesions can be seen: subcutaneous nodules, palpable and nonpalpable purpura, red or gray macules, red or gray papules, macules or papules with progressive central necrosis, flaccid pustules, vesicles, and hemorrhagic bullae. The most characteristic skin lesions encountered in disseminated fusariosis are the "ecthyma gangrenosum-like" lesions, which are red or gray macules with central ulceration or black eschar (see Fig. 1).[4,5,59,60] Fusarium skin lesions are often tender, especially subcutaneous nodules, and can involve any skin site, although they appear predominantly in the extremities (see Fig. 1).[59,60] Most patients have lesions at different stages of evolution, and the number of lesions is highly variable.[59,60] Accompanying myalgia is also common, reflecting concomitant muscle involvement.[4,5]

 

 

Figure 1. (A, B) Typical Fusarium skin lesions: note the small diameter of lesions (typically 1 cm), the presence of lesions at different stages of evolution, and the large number of lesions. Also note the characteristic "ecthyma gangrenosum-like" lesion, which is a red or gray macule with central ulceration or black eschar. [Patient in (B) also has petechial rash due to thrombocytopenia, which is unrelated to the Fusarium lesions.] © Typical Aspergillus skin lesion: note the greater diameter of this necrotic lesion compared with the Fusarium lesions. Also, note that Aspergillus skin lesions are fewer in number (often a single lesion), less widespread, and present as a black eschar with a thinner (compared with Fusarium lesions) erythematous halo. Note: Fusarium and Aspergillus skin lesions do not always manifest these characteristic patterns, and atypical presentations frequently occur.

Fusarium skin lesions are different from those encountered in disseminated IA (see Fig. 1). Specifically, Aspergillus skin lesions tend to be fewer in number, larger (2-3 cm versus 1 cm in diameter), and less widespread, and they usually consist of a black eschar with a thinner erythematous halo (see Fig. 1).[60] Fusarium skin lesions encountered in immunosuppressed patients are also different from those seen in immunocompetent hosts, in whom they are fewer in number and localized, typically follow skin breakdown (i.e., after trauma, insect bites, or onychomycosis), and exhibit diverse histopathologic features (marked inflammation and neutrophil infiltration with scant hyphal elements compared with the marked necrosis and vascular invasion, abundant hyphae, and paucity of neutrophil infiltration and inflammation seen in skin lesions in immunocompromised hosts).[59,60]

Antifungal Susceptibility-Treatment Fusarium is one of the most resistant fungi to the arsenal of modern antifungal agents.[2,4-8,61-64] In particular, F. solani is the most resistant species within the genus.[61-64] The molecular mechanisms responsible for this high resistance have not been studied thus far.[65] Given the inherent resistance of Fusarium spp. to the current armamentarium of antifungal agents and the profound net state of immunosuppression in patients who typically develop fusariosis, the current therapeutic strategies for invasive fusariosis in heavily immunocompromised patients are problematic.[2,4,5,7-12] Also, in view of the rarity of fusariosis, most of the experience with it is derived from uncontrolled case series, the majority of which have been confounded by several critical factors, such as recovery of neutrophil count.[4,5,48] Thus management of fusariosis is not well defined and is highly individualized.[5,48] Table 2 summarizes the current controversies in the management of fusariosis.

The mainstay in the treatment of fusariosis has traditionally been AMB. However, the in vitro susceptibility of Fusarium spp. to AMB is, at best, mediocre.[2,4,61-64] Most studies have reported that the minimal inhibitory concentration of AMB against Fusarium spp. is greater than 1 µg/mL. Hence, such minimal inhibitory concentration values are higher than the reported tissue concentration of AMB in the lungs (0.5 mg/mL) when using conventional intravenous AMB doses (1.0-1.5 mg/kg/d).[66] It is unclear, though, whether the in vitro susceptibility of Fusarium spp. alone can predict outcome because other factors, such as neutrophil recovery, are probably the most critical determinants of the prognosis for fusariosis.[5,9,67]

The activity of AMB in animal models of fusariosis is also limited.[62,63] In fact, only high doses of liposomal AMB have been shown to be active against Fusarium spp. in animal models using immunocompetent mice.[68] Specifically, administration of liposomal AMB at 10 to 20 mg/kg/d resulted in a significantly reduced fungal burden in the spleen and liver of mice infected with Fusarium verticilloides. In contrast, AMB deoxycholate was not efficacious in other models of fusariosis.[62,63] However, due to a lack of other therapeutic options, high doses of AMB are currently used in clinical practice.[4,5,7,8] Following the introduction of lipid formulations of AMB, the use of high AMB doses is now feasible with less toxicity when compared with AMB deoxycholate, and there have been reports of better outcome of fusariosis using high-dose AMB regimens. Specifically, Walsh et al[69] reported that the mortality rate in patients to whom they administered high doses of AMB lipid complex (>5 mg/kg/d) was significantly lower (<30%) than that observed in patients receiving conventional AMB doses (>75%). Confounding factors that were not addressed in this cohort of patients, such as recovery of neutrophils, do not allow for firm conclusions regarding the true efficacy of AMB lipid complex, however. Also of concern is that recent pharmacodynamic studies have suggested that due to the fact that AMB is highly lipophilic and binds excessively to proteins, the maximum achievable free-drug concentration of AMB in tissues does not exceed 0.7 µg/mL, even with very high AMB dosing.[70,71] Hence, it is unclear whether greatly increasing the AMB dose translates to a respective increase in the free-drug concentration that can be achieved in tissues.[70]

Natamycin is also active against Fusarium spp. both in vitro and in vivo.[2,7,72,73] In fact, natamycin, along with AMB, has been the mainstay of treatment for Fusarium keratitis.[72,73] However, its toxicity precludes systemic use of it in clinical practice. Furthermore, nystatin, another polyene antifungal, has shown to be effective in halting the progression of fusariosis in pediatric patients with severe burns when used topically in powder form at a high concentration (6 × 106 U/g).[74]

Ketoconazole, miconazole, fluconazole, and itraconazole have no in vitro activity against Fusarium spp.[61,63] However, the newer broad-spectrum triazoles voriconazole (VRC), posaconazole, and ravuconazole have variable in vitro activity against Fusarium spp. and show promise for the management of fusariosis.[75-83] Among these new-generation triazoles, VRC, which was recently approved by the U.S. Food and Drug Administration for the treatment of refractory fusariosis, is the most active in vitro against Fusarium spp. Nonetheless, its activity is species dependent. Specifically, VRC is more active and is fungicidal against non-solani Fusarium spp., whereas its activity is fungistatic and less pronounced against F. solani. Thus, when compared with AMB, VRC does not have superior in vitro activity, especially against F. solani.[61,63,75-83] Besides its in vitro activity, VRC is also efficacious in animal models of fusariosis.[83] Furthermore, Perfect et al[84] reported that VRC resulted in a favorable response in five (45%) of 11 patients with fusariosis refractory to or intolerant of standard therapy. The 90-day Kaplan-Meier estimate of proportional survival of 0.71 in that study is also noteworthy because in our experience at the University of Texas M. D. Anderson Cancer Center the 90-day survival was 29% in patients with fusariosis treated with AMB-based regimens.[35] Another advantage of using VRC in that study was the low incidence of adverse effects.[84] In addition, VRC was recently reported to be effective in an AMB-breakthrough case of disseminated fusariosis that occurred in a patient with leukemia in the setting of neutropenia.[85] Following completion of VRC treatment, no relapses of fusariosis were noted despite the subsequent reinstitution of induction chemotherapy cycles.[85]

Posaconazole, an investigational broad-spectrum triazole, is also active against Fusarium species both in vitro and in animal models.[80,82] The preliminary experience with posaconazole in our institution indicates that ~50% of patients with fusariosis refractory to or intolerant of standard treatment modalities responded to this triazole.[86] Other investigational azoles, such as CS-758 and UR-9825, are also variably active in vitro against Fusarium.[87,88] Fusarium spp. are inherently resistant to the echinocandins caspofungin (CAS), micafungin, and anidulafungin.[89-92] Nonetheless, CAS was recently reported to result in resolution of AMB-breakthrough Fusarium fungemia in a patient with acute leukemia.[93] Fusarium spp. are also resistant to nikkomycin Z, an inhibitor of chitin synthesis in the fungal cell wall.[94] In contrast, other agents have shown in vitro activity against Fusarium spp. For example, we recently demonstrated that pentamidine is fungicidal in vitro against non-solani Fusarium spp., whereas it has in vitro fungistatic effects against F. solani.[95] Terbinafine has also shown in vitro activity against some non-solani Fusarium spp.[96] Finally, selected aromatic dicationic compounds have also shown in vitro activity against F. solani.[97] Hence, further in vivo studies and clinical data are required to investigate the potential of the aforementioned investigational agents in the management of fusariosis.

In view of the inherent resistance of Fusarium spp. to most antifungal agents, AMB-based combination regimens have also been suggested or used for fusariosis. For example, use of 5-flucytosine (5-FC) has been proposed to result in an additive interaction with AMB.[98] Therefore, the combination of AMB deoxycholate at a dose of 1.5 mg/kg /d with 5-FC at a dose of 25 mg/kg given every 6 hours (adjusted to achieve a maximum serum level of <60 µg/mL) has occasionally been used. However, no controlled studies have shown a true benefit of using AMB with 5-FC versus AMB alone; actually, this combination has shown no activity in a murine model of disseminated fusariosis.[63] Moreover, the myelosuppressive properties of 5-FC are of concern.[98] Arikan et al[99] showed a modest in vitro additive interaction of AMB with CAS; however, no in vivo data have supported this concept. Combinations of AMB with rifampin and azithromycin are also synergistic in vitro.[100,101] However, the former combination has been unsuccessful in the treatment of fusariosis in clinical practice, whereas further in vivo data are required to explore the potential of the latter. Given that AMB and VRC are the most active agents against Fusarium spp., a strategy combining a lipid formulation of AMB with VRC should be explored further.Because the neutrophil count seems to be the most crucial prognostic determinant in fusariosis cases, a potentially beneficial adjuvant therapeutic strategy is the use of recombinant granulocyte colony-stimulating growth factor and granulocyte-macrophage colony-stimulating factor and /or granulocyte transfusion from granulocyte colony-stimulating growth factor-stimulated donors and granulocyte-macrophage colony-stimulating factor-stimulated donors.[102,103] It has been suggested that granulocyte transfusion results in more favorable response rates (33-50%) in profoundly neutropenic patients by shortening the duration of neutropenia.[4,11] However, the presence of confounding factors such as achieving remission of the underlying malignancy, bone marrow recovery, and the extent of infection (localized versus disseminated fusariosis) may have led to overestimation of the impact of this intervention. Of note, it was recently shown that interferon-γ and interleukin-15 enhance the ability of neutrophils to cause hyphal damage against F. solani and F. oxysporum, suggesting a potential adjunct role for these cytokines in the management of fusariosis.[104,105]Finally, in patients with hematologic malignancies, Fusarium onychomycosis should be treated aggressively, including nail removal and systemic antifungal therapy.[25] Overall, surgical resection of infected necrotic tissue, such as abscesses, sinusitis, and soft tissue infections, is a significant component of therapy for fusariosis.[4,25,26,106] When a CVC-related Fusarium infection is suspected, prompt removal of the catheter should also be attempted to prevent further dissemination.[23,24]In conclusion, taking into consideration the suboptimal efficacy of modern antifungals against Fusarium spp., a high index of suspicion is required for prompt diagnosis of fusariosis. Thus invasive fusariosis should be considered in febrile patients with hematologic malignancies and neutropenia who have any of the following characteristics: (a) a paronychia with or without onychomycosis, (b) a digital ulcer or eschar, and © widespread erythematous tender skin lesions with associated myalgia. In such cases, a thorough work-up should be done, including blood culture analysis, radiographic evaluation of the sinuses and lungs (using computed tomography), and skin biopsy for cultures, histopathologic examination, and fungal staining. Following establishment of the diagnosis, early initiation of aggressive treatment with high doses of AMB (with or without VRC) along with vigorous efforts to shorten the duration of neutropenia and taper immunosuppressive regimens should be attempted.Tables Table 1. Similar Characteristics and Major Differentiating Features of Invasive Aspergillosis and Invasive Fusariosis

 

 

 

 

Common Characteristics of Invasive Aspergillosis and Invasive Fusariosis

 

Differentiating Features of Invasive Aspergillosis and Invasive Fusariosis

 

Similar clinical presentation (fever despite use of broad-spectrum antibiotics, sinopulmonary infection).

Skin lesions are more common in disseminated fusariosis (50–70%) than in disseminated invasive aspergillosis (IA) (<10%).

 

Similar histopathology (angioinvasion, acute branching septate hyphae).

Skin lesions are different in fusariosis and IA (Aspergillus skin lesions are fewer, less widespread, have a larger diameter, and present with a black eschar with a thinner erythematous halo).

 

Similar radiographic presentation (subpleural nodular opacities, cavitation).

Fungemia is more common in fusariosis (60–70%) than in IA (<5%). Fungemia also often occurs earlier in fusariosis than in IA (shortly before death or after death).

 

Aspergillus and Fusarium molds are ubiquitous in the environment. High mortality rate (>70%).

Fusarium spp. are highly resistant to antifungal agents. Myalgias are more common in fusariosis. Table 2. Controversies in the Management of Fusariosis

 

Is there a role for voriconazole in initial therapy? What is the role and the optimal dose of lipid formulations of amphotericin B (AMB) in primary therapy for fusariosis? What is the most cost-effective lipid formulation of AMB for the management of fusariosis? Is the dose intensity more important than the cumulative dose of AMB? Will the new investigational triazoles (e.g., posaconazole) live up to their promise? What is the future of combination therapy for fusariosis (AMB plus voriconazole, AMB plus caspofungin)? Does speciation of Fusarium spp. hold prognostic significance? What is the role of susceptibility testing for Fusarium spp.? What is the role of immunomodulators in the management of fusariosis? Is there effective prophylaxis for fusariosis? What is the role of adjunctive surgery in the management of fusariosis? References

 

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